Immediate release tablet or solution: Adults ≥17 years: Initial: 500 mg twice daily or 850 mg once daily; titrate in increments of 500 mg weekly or 850 mg every other week; may also titrate from 500 mg twice a day to 850 mg twice a day after 2 weeks

If a dose >2000 mg daily is required, it may be better tolerated in 3 divided doses. Maximum recommended dose: 2550 mg daily.

Transfer from other antidiabetic agents: No transition period is generally necessary except when transferring from chlorpropamide. When transferring from chlorpropamide, care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

Concomitant metformin and oral sulfonylurea therapy: If patients have not responded to 4 weeks of the maximum dose of metformin monotherapy, consider a gradual addition of an oral sulfonylurea, even if prior primary or secondary failure to a sulfonylurea has occurred. Continue metformin at the maximum dose. If adequate response has not occurred following 3 months of metformin and sulfonylurea combination therapy, consider switching to insulin with or without metformin.

Failed sulfonylurea therapy: Patients with prior failure on glyburide may be treated by gradual addition of metformin. Initiate with glyburide 20 mg and metformin 500 mg daily. Metformin dosage may be increased by 500 mg/day at weekly intervals, up to a maximum metformin dose (dosage of glyburide maintained at 20 mg daily).

Children 10-16 years: Initial: 500 mg twice daily; increases in daily dosage should be made in increments of 500 mg at weekly intervals, given in divided doses, up to a maximum of 2000 mg daily

Children ≥17 years: Refer to adult dosing.

Dosing: Geriatric

The initial and maintenance dosing should be conservative, due to the potential for decreased renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin. Do not use in patients ≥80 years of age unless normal renal function has been established.

Dosing: Renal Impairment

The plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. Per the manufacturer, metformin is contraindicated in the presence of renal dysfunction defined as a serum creatinine ≥1.5 mg/dL in males, or ≥1.4 mg/dL in females and in patients with abnormal clearance. The Canadian labeling recommends that metformin be avoided in patients with Cl cr <60 mL/minute.

Dosing: Hepatic Impairment Avoid metformin; liver disease is a risk factor for the development of lactic acidosis during metformin therapy.

Hypersensitivity to metformin or any component of the formulation; renal disease or renal dysfunction (serum creatinine ≥1.5 mg/dL in males or ≥1.4 mg/dL in females) or abnormal creatinine clearance from any cause, including shock, acute myocardial infarction, or septicemia; acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis)

Warnings / Precautions Drug

Concerns related to adverse effects:

• Cardiovascular mortality: Administration of oral antidiabetic drugs has been reported to be associated with increased cardiovascular mortality; metformin does not appear to share this risk.

• Lactic acidosis: [U.S. Boxed Warning]: Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in clinical situations predisposing to hypoxemia, including conditions such as cardiovascular collapse, respiratory failure, acute myocardial infarction, acute congestive heart failure, and septicemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

Disease-related concerns:

• Heart failure: Use caution in patients with congestive heart failure requiring pharmacologic management, particularly in patients with unstable or acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion.

• Hepatic impairment: Avoid use in patients with impaired liver function due to potential for lactic acidosis.

• Renal impairment: Metformin is substantially excreted by the kidney; patients with renal function below the limit of normal for their age should not receive therapy. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Special populations:

• Elderly: Metformin should not be initiated in patients ≥80 years of age unless normal renal function is confirmed.

• Iodinated contrast: Therapy should be temporarily discontinued prior to or at the time of intravascular administration of iodinated contrast media (potential for acute alteration in renal function). Metformin should be withheld for 48 hours after the radiologic study and restarted only after renal function has been confirmed as normal.

• Surgical procedures: Therapy should be suspended for any surgical procedures (resume only after normal oral intake resumed and normal renal function is verified).

Corticosteroids (Orally Inhaled): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy

Corticosteroids (Systemic): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy

Dalfampridine: May increase the serum concentration of MetFORMIN. MetFORMIN may increase the serum concentration of Dalfampridine. Risk C: Monitor therapy

Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Withhold metformin from all patients receiving intravascular iodinated contrast agents prior to or at the time of the procedure and for at least 48 hrs thereafter. Document adequate renal function before restarting metformin. Risk D: Consider therapy modification

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Risk C: Monitor therapy

Adverse events have not been observed in animal studies; therefore, metformin is classified as pregnancy category B. Metformin has been found to cross the placenta in concentrations which may be comparable to those found in the maternal plasma. Pharmacokinetic studies suggest that clearance of metformin may be increased during pregnancy and dosing may need adjusted in some women when used during the third trimester.

Fetal, neonatal, and maternal outcomes have been evaluated following maternal use of metformin for the treatment of GDM and type 2 diabetes. Available information suggests that metformin use during pregnancy may be safe as long as good glycemic control is maintained; however, many studies used metformin during the second or third trimester only. Maternal hyperglycemia can be associated with adverse effects in the fetus, including macrosomia, neonatal hyperglycemia, and hyperbilirubinemia; the risk of congenital malformations is increased when the Hb A 1c is above the normal range. Diabetes can also be associated with adverse effects in the mother. Poorly-treated diabetes may cause end-organ damage that may negatively affect obstetric outcomes. Physiologic glucose levels should be maintained prior to and during pregnancy to decrease the risk of adverse events in the mother and the fetus. Until additional safety and efficacy data are obtained, the use of oral agents is generally not recommended as routine management of GDM or type 2 diabetes mellitus during pregnancy. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.

Metformin has also been evaluated for the treatment of PCOS, a syndrome which may exhibit oligomenorrhea and, in some women, hyperinsulinemia. It is not recommended as first-line therapy; when used to treat infertility related to PCOS, current guidelines restrict the use of metformin to women with glucose intolerance. Because ovulation rates will likely improve in women with PCOS who are taking metformin, appropriate contraceptive measures should be discussed in women who are not attempting to conceive.

Lactation

Enters breast milk/not recommended

Breast-Feeding Considerations

Low amounts of metformin (generally ≤1% of the weight-adjusted maternal dose) are excreted into breast milk. Breast-feeding is not recommended by the manufacturer. Because breast milk concentrations of metformin stay relatively constant, avoiding nursing around peak plasma concentrations in the mother would not be helpful in reducing metformin exposure to the infant. Growth and development were not affected in infants born to mothers with PCOS and who took metformin while breast-feeding.

Monitoring Parameters

Urine for glucose and ketones, fasting blood glucose, hemoglobin A 1c , and fructosamine. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function should be performed, at least annually. While megaloblastic anemia has been rarely seen with metformin, if suspected, check vitamin B 12 and folate if anemia is present.

Reference Range

Recommendations for glycemic control in nonpregnant adults with diabetes (ADA, 2012):

Hb A 1c : <7% (a more aggressive [<6.5%] or less aggressive [<8%] Hb A 1c goal may be targeted based on patient-specific characteristics)